tbuckley/cabot-search huggingface dataset:
P11.56.A MODIFIED FRAILTY INDEX (MFI) AS A SURVIVAL AND FUNCTIONAL OUTCOME PREDICTOR IN OLDER PATIENTS UNDERGOING SURGERY FOR BRAIN METASTASES
Authors: T F Ersoy, D Brainman, R Coras, M Simon
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Surgical decision making in older patients with brain metastases (BM) is challenging. Frailty and comorbidities are often thought to limit therapeutic options as well as functional and survival outcomes. MATERIAL AND METHODS 139 consecutive patients undergoing surgery 2017-2021 for BM were analyzed retrospectively. Cut-off for age was ≥60 yrs. in accordance with the graded prognostic assessment (GPA) index. Frailty was investigated using the mFI index, a compound measure assessing comorbidities and the patients’ functional health status. RESULTS Median age was 69.0 (IQR: 63.0-74.5) yrs. 55.4% had multiple metastases. We recorded 9.4% major (CTCAE III-V) surgical and 10.1% medical complications. 7.9% of patients had major new focal neurological deficits ≥30 days. Median overall survival (mOS) was 7.8 (IQR: 5.0-10.6) months. Frailer patients lived shorter (mOS for “least-frail”/mFl 0: 13.6 [IQR: 8.6-18.6], “moderately frail”/mFl 1-2: 9.0 [IQR: 4.9-13.0] and “frailest”/mFl ≥3: 2.7 [IQR: 0.9-4.5] months; p&amp;lt;0.001). Multivariate analysis with all parameters correlating significantly with mOS in the univariate analysis (mFI, higher preop. KPS, younger age [&amp;lt;69 yrs.], female sex) revealed a higher preop. KPS to be the only independent significant survival predictor (70 vs. 80-100; HR 2.1, p&amp;lt;0.001). Frailer patients had poorer functional outcomes (patients w/ postop. KPS ≤70 vs. 80-100; mFI 0: 9/36 [25.0%], mFI 1-2: 20/65 [30.8%], mFI ≥3: 25/38 [65.8%]; p&amp;lt;0.001). Multivariate analysis with all parameters correlating significantly with better functional outcome in the univariate analysis (mFI, higher preop. KPS, younger age, female sex and single metastasis) showed that a higher preop. KPS was the strongest prognostic parameter (RR 17.2, p&amp;lt;0.001). The mFI was not an independent outcome predictor. In a ROC analysis the preoperative KPS proved a much better predictor of functional outcome than the mFI (AUC 92 vs. 71%; sensitivity/specificity optimum 80 vs. 2, resp.). mFI was not a predictor of complications (p=NS). CONCLUSION The mFI proved a strong survival and functional outcome predictor in older patients. However, this effect was no longer seen in multivariate analyses when the KPS was included as a covariate. This may suggest that surgical outcomes depend on the patients’ presurgical functional health status rather than comorbidities. The presence of comorbidities (if well treated) should therefore not deter from BM surgery in older patients.
P09.09.A RESECTION CAVITY LOCATIONS ASSOCIATED WITH CHANGES IN DEPRESSIVE SYMPTOMS AFTER SURGERY IN PATIENTS WITH DIFFUSE GLIOMA
Authors: V Belgers*, M N G van Genderen*, M Cakmak, L Douw, F Barkhof, M Klein, J M Niers, R S Eijgelaar, P C De Witt Hamer
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The aim of glioma resections is to maximize tumor removal while preserving functional integrity. Functional outcome usually focuses on neurological and neurocognitive functions. However, emotions may also be affected by surgery. Therefore, we determined the occurrence of depressive symptoms after surgery and investigated factors associated with changes in depressive symptoms after surgery, specifically focusing on the location of the resection cavity. MATERIAL AND METHODS This study included a single center retrospective cohort of patients with a diffuse glioma who underwent a surgical resection between 2009 and 2021. Patients completed the Center for Epidemiologic Studies Depression Scale (CES-D) before and after surgery, with cut-offs for no depressive symptoms (CES-D &amp;lt;16), mild depressive symptoms (CES-D 16-20) or moderate to severe depressive symptoms (CES-D &amp;gt;20). We calculated a change score with a minimum clinically important difference defined as 6 points. Surgical cavities were semi-automatically segmented based on postoperative MRIs. Patient characteristics, i.e. age, sex, education, epilepsy, and tumor characteristics, including tumor grade, and segmented cavity locations, were related to change in depression scores in a multivariable regression analysis and sparse canonical correlation analysis. RESULTS We included 83 patients with a mean age of 42 years (SD 11.8), consisting of 61% males, 49% with high education, 86% with epilepsy and 61% with a WHO grade 2 glioma, 27% grade 3 and 12% grade 4 glioma. Median change in depressive scores was 1, with a range from -25 to 30. Before surgery, 26% had at least mild depressive symptoms, after surgery, 33% had at least mild depressive symptoms. A clinically important increase (≥6) in depressive symptoms was seen in 25% of patients, whereas 15% had a clinically important decrease in depressive symptoms. Patient characteristics and tumor grade were not associated with change in depressive symptoms. Eight clusters of cavity locations were associated with change in depressive symptoms (CV corr = 0.224, p = 0.0419), including in the left and right frontal, temporal, and anterior cingulate regions. CONCLUSION Resection cavity locations are associated with changes in depressive symptoms in patients with diffuse glioma. This may be important for patient counseling and of potential use for neurosurgical decision making. * These authors contributed equally
P06.14.A DIAGNOSIS AND MANAGEMENT OF NEUROPATHIES RELATED TO IMMUNE CHECKPOINT INHIBITORS: A CASE SERIES
Authors: S Cuzzubbo, P Lozeron, B Baroudjian, F D’Oria, P Tétu, R Ursu, V Gounant, E Meppiel, T Lambert, S Ng Wing Tin, B Duchemann, C Belin, C Lebbé, A F Carpentier
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Immune checkpoint inhibitors (ICIs) are associated with a wide range of neurotoxicities. Several types of neuropathies have been associated to immune checkpoint inhibitors (ICIs), from length-dependent sensory neuropathies to radiculoneuropathies similar to Guillain-Barré syndromes, with an overall incidence estimated to be between 0.1-1.2% of patients. Guidelines recommend prompt ICI discontinuation and the INTRODUCTION of steroids depending on the severity of the adverse event. However, the usage of IVIG or plasmapheresis (alternatively or in addition to steroids) has been reported in cases of Guillain-Barré-like syndromes. MATERIAL AND METHODS In this study, we report a retrospective consecutive series of patients with an ICI-related neuropathy referred to our department between 2016 and 2021, with the intent to describe their clinical and para-clinical features and the outcome after ICI discontinuation and steroids. RESULTS We identified 12 cases of acute peripheral nervous system involvement, with a predominant sensory pattern. The median onset of symptoms from ICI initiation was 18 weeks, and the median number of ICIs doses was 3. Electrophysiological studies, done in 11 patients, showed a radiculopathy in 9 cases, associated with an axonal neuropathy in 3, and a demyelinating neuropathy in 2 cases. Altogether, these findings are consistent with Guillain-Barré-like syndrome. ICIs were stopped in all patients and steroids started in 7 patients, leading to a favourable outcome (complete recovery =7, partial recovery =4, stability =1). CONCLUSION This consecutive retrospective series identifies Guillain-Barré-like syndrome as the main clinical pattern of immune related neuropathies. We did not observe any case of length-dependent axonal neuropathy without an associated root involvement. Our systematic management, consisting of ICI discontinuation in all patients and steroids in more severe cases, seems a valid strategy. On the other hand, our results do not support the use of IVIG or other treatments.
P06.01.A HAS THE USE OF DUAL AGENT IMMUNOTHERAPY BEEN ALTERING THE INCIDENCE OF MELANOMA BRAIN METASTASES? A POPULATION-LEVEL ANALYSIS AND SINGLE-INSTITUTION VALIDATION
Authors: S Salmanian, D Bhanja, H Wilding, C Moeckel, J Hong, J Dao, A Baroz, C Stahl, J Sivik, J Drabick, C Pameijer, A Mansouri
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Dual agent immunotherapy (dIT) has revolutionized the treatment of advanced melanoma, with recent clinical trials demonstrating its effectiveness in managing small, asymptomatic melanoma brain metastases (MBM) in the upfront setting. However, its potential role in preventing MBM has not been thoroughly investigated. MATERIAL AND METHODS A retrospective analysis was performed on the TriNetX database, which compiles clinical data from 92 healthcare organizations. Melanoma patients without MBM at diagnosis were divided into two groups: those who received ipilimumab alone (single immunotherapy, sIT) and those who received ipilimumab and nivolumab (dIT). The study compared the frequency of new asynchronous MBM diagnosis among the cohorts and analyzed the median overall survival (OS) of MBM patients using Kaplan Meier analysis and log-rank tests. Additionally, a retrospective cohort validation study was conducted on a sample of randomly selected patients treated at a single institution between 2012-2019. Electronic medical records were reviewed for demographics, melanoma treatment history, and clinical outcomes. RESULTS TriNetX identified a total of 732,555 melanoma patients, including 717,408 who did not receive immunotherapy (no-IT), 4,585 who received dual immunotherapy (dIT), and 4,101 who received single immunotherapy (sIT). The mean ages at melanoma brain metastases (MBM) diagnosis were 66.9, 61.5, and 63.2 years for each respective group. The prevalence of MBM was 1.5%, 9.6%, and 15.6% for no-IT, dIT, and sIT groups, respectively (p &amp;lt; 0.0001). DIT was associated with a lower rate of MBM compared to sIT(OR [95%CI], 0.64 [0.61-0.77]). After propensity score matching, the median overall survival for MBM patients was not statistically different between the no-IT, dIT, and sIT groups (347, 400, 414 days, respectively). In the validation group of 90 patients (30 no-IT, 27 sIT, 34 dIT), predominantly male (61.5%), stage III (62.5%), the prevalence of MBM was 13.8%, 59%, and 38.2% for each respective group for developing MBM (OR [95%CI], 2.35 [0.84-6.60], p=0.08). The mean time between immunotherapy initiation and MBM was 305 days for dIT and 500 days for sIT for patients who developed MBM. CONCLUSION The results suggest that using a combination of ipilimumab and nivolumab immunotherapy could be effective in reducing the incidence of brain metastases in advanced melanoma patients. Further investigation is needed to explore the potential preventive role of dIT in MBM development in this patient population.
P13.13.B INTERPRETABLE WHOLE SLIDE IMAGE PROGNOSTIC STRATIFICATION OF GLIOBLASTOMA PATIENTS FURTHERING DISEASE UNDERSTANDING
Authors: B Baheti, S Innani, G Mehdiratta, M P Nasrallah, S Bakas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is the most common malignant adult brain tumor, with a grim prognosis and heterogeneous morphology. Stagnant patient prospects over the last 20 years reflect our limited disease understanding. Robust prognostic patient stratification from whole slide images (WSI) using interpretable computational methods could improve disease understanding and patient management. MATERIAL AND METHODS Assessment of the TCGA-GBM and TCGA-LGG data collections by the 2021 WHO classification criteria of CNS tumors identified 188 glioblastoma (IDH-wt, grade 4) cases, divided into short (&amp;lt;9 months, n=94) and long (&amp;gt;13 months, n=94) survivors. An H&amp;E-stained WSI from each patient is selected and comprehensively pre-processed to remove artifactual and non-tissue regions by partitioning them into 256x256 patches. An interpretability mechanism via a weakly supervised attention-based multiple-instance-learning algorithm is leveraged for prognostic stratification. The attention scores are visualized as a heatmap to identify the essential ROIs driving decisions. The model is evaluated on 10-fold monte carlo cross-validation, using training (80%), validation (10%), and test (10%) sets. RESULTS Quantitative evaluation revealed ValidationACCURACY=70%, TestACCURACY =62%, ValidationAUC= 0.75, and TestAUC=0.68. Heatmaps indicate weight given throughout histologically malignant areas for correctly predicted long survivors, including necrosis, hypercellularity, atypia, infiltration, and proliferation. Correct prediction of short survival weighted infiltrative features, including leptomeningeal involvement. For misclassified long-survivors, necrotic areas are not heavily weighted, and gemistocytic cells are seen in a densely packed rather than infiltrating arrangement. For some misclassified short-survivors, the hot regions are hypercellular; however, these are a minority of the specimen, which predominantly showed a less cellular, fibroblastic, spindled appearance. CONCLUSION The interpretation of algorithmic decisions through qualitative visualization of heatmaps can offer insights into histologic regions with prognostic relevance. In the case of glioblastoma, the histologic appearance of long survivors based on a neuropathologist's observation suggests aggressive tumors traditionally considered indicative of poor prognosis. The algorithm's ability to accurately predict long survival based on these areas indicates that further investigation of these features may be warranted for improved prognostication through histologic assessment. Our findings support the use of data-driven interpretation of algorithmic decisions to identify morphological patterns with prognostic significance, which would further our understanding of glioblastoma.
OS09.1.A<i>IN VIVO</i>TWO-PHOTON TUMOR IMAGING IN AN ORTHOTOPIC MEDULLOBLASTOMA MOUSE MODEL
Authors: N Teske, N N Kutlu, J J Herold, L Dengler, C Eberle, E Nikolaishvili, P Karschnia, J Blobner, K Müller, S Langer, V Buschinger, L Warmuth, D H Busch, V R Buchholz, N Thon, J Tonn, T Feuchtinger, L von Baumgarten
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Medulloblastoma represents the most common primary brain malignancy in pediatric patients and is associated with neuro-cognitive impairment and frequent relapses after aggressive multimodal therapy. Adoptive immunotherapies such as CAR T-cell therapy are currently being investigated, showing promising results in preclinical models but lacking efficacy in first-in-human trials. Refined in vivo models to investigate reasons for treatment failures are therefore urgently needed. METHODS We developed a xenogeneic orthotopic medulloblastoma (MB) model in mice by combining a chronic cerebellar window with repetitive intravital two-photon laser scanning microscopy. Red tdTomato-fluorescent DAOY (SHH MB) tumor cells expressing EphA2 were implanted intracranially into the cerebellum of immunodeficient mice (n = 7), and tumor cell formation was followed by in vivo-microscopy. Intravenous fluorescein isothiocyanate (FITC)-dextran was used for intravascular plasma staining. EphA-directed CAR T-cells were injected into the adjacent brain parenchyma. RESULTS Chronic cranial window implantation was well tolerated and allowed repetitive visualization of the mouse cerebellum. After intracranial tumor cell implantation, continuous tumor growth could be evaluated with epifluorescence as well as 2-photon laser scanning microscopy. Tumor formation was identified as early as day 5 in every mouse and could continuously be followed up to 35 days until mice succumbed due to tumor burden. Window quality and fluorescence intensity remained high until the end of the experiments. Studies on GFP-expressing CAR T-cell injection directed against EphA2 are currently ongoing. CONCLUSIONS We herein establish a robust orthotopic medulloblastoma mouse model that allows repetitive in vivo tracking of fluorescence-expressing tumor cells, CAR T-cells and blood vessels over weeks. Such models may be used to study medulloblastoma tumor growth under the influence of different immunotherapies and reveal interactions between tumor cells and CAR T-cell therapies on a single-cell level.
P07.11.B A NOVEL CRISPR/CAS9 KNOCKOUT LIBRARY UNCOVERS PAN-ESSENTIAL MIRNAS IN HUMAN CANCER CELL LINES
Authors: D J Merk, L Paul, F Tsiami, H Hohenthanner, G Mohseni-Kouchesfahani, B Walter, L A Haeusser, A Brown, N S Persky, D E Root, G Tabatabai
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play an important role during cancer initiation and progression. Genome-wide functional screening using the CRISPR/Cas9 system is a powerful tool to uncover genetic dependencies for distinct tumor entities, and has revealed novel insights into pan-cancer fitness genes. Current libraries are focused on single guide RNAs (sgRNAs) targeting protein-coding genes, thereby limiting functional genomics-based investigations of miRNA function. MATERIAL AND METHODS We here designed a novel CRISPR/Cas9 knockout library of 8,107 distinct sgRNAs targeting a total of 1,769 human miRNAs. Using a total of 45 human cancer cell lines, representing 16 different tumor entities, we performed negative selection screens to identify miRNA fitness genes. Screen hits per cell line were scored on the basis of a combination of a supervised Bayesian gene essentiality analysis (BAGEL2) and an unsupervised gene ranking algorithm (MAGeCK). miRNA genes that scored across all cell lines, i.e. potentially pan-essential miRNAs, were identified using a combination of the Adaptive Daisy Model (ADaM) algorithm and the Fitness Percentile (FiPer) method. RESULTS In silico analyses revealed that our library has significantly lower off-target activity for protein-coding genes as compared to previously described miRNA-targeting sgRNA libraries, while providing a higher coverage of miRNAs present in the human genome. In total, only 13% (n=230) of all targeted miRNAs induced a fitness effect on one or more cell lines, and the majority (83%) of these genes induced a dependency in less than 50% of the tested cell lines. Pan-cancer fitness gene detection by ADaM or FiPer differed solely on the level of stringency. As such, ADaM and FiPer identified 34 core fitness or 54 common essential miRNAs, respectively, and almost all core fitness genes (97%) were identified as common essential. Preliminary network analyses revealed that protein-coding genes that are regulated by core fitness miRNAs are significantly enriched for cell cycle and p53 signaling networks, providing a first rationale for their dependency profiles in human cancer cell lines. CONCLUSION We here established a novel method for functional investigation of miRNAs by means of genome-wide CRISPR/Cas9 knockout screens. Our sgRNA library outperforms previously established libraries in terms of specificity and overall miRNA coverage, making it a novel tool to investigate miRNA function in a genome-wide fashion. We here use this library to define a first-of-its-kind genome-wide functional annotation of miRNAs, revealing a subset of pan-cancer fitness miRNAs that might regulate essential cellular processes such as cell cycle progression. Our data highlight the wide potential of this library in investigating miRNA function in diverse biological settings.
P22.04.B THE VALUE OF A NURSE CARE COORDINATOR WORKING WITH YOUNG BRAIN TUMOR PATIENTS IN THE NEUROSURGICAL OUTPATIENT CLINIC
Authors: M Bruun-Pedersen, R Guldager, S M J Nordentoft, J Skjøth-Rasmussen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND When young people between 18-35 are diagnosed with a brain tumor, it often has significant impact on their lives. In that period the young person is often in their process of building their lives, with little to no mental preparation on perspectives towards end of life. The aim of this study is to measure the value of a Nurse Care Coordinator, working with young brain tumor patients in the Neurosurgical Outpatient Clinic. MATERIAL AND METHODS The Nurse Care Coordinators function is to support and guide the young patients, from getting the diagnosis with a brain tumor and through their disease and treatment. The Nurse Care Coordinator meets the young patient and relatives several times from before surgery, and for as long as needed, depending on the patients’ individual situation. The relation and interactions with the young patients are very individually approached. However, the fundamental approach to all young patients includes regular weekly phone calls, which eventually become monthly conversations or personal meetings in the Outpatient Clinic, all depending on the topic and young patient’s preferences. Areas where the Nurse Care Coordinator can assist the young patients includes general overviews of their disease and treatment course, assist where barriers may arise and ensuring correct rehabilitation for the young patients, offering an elaborating conversation on the diagnosis, or discuss solutions with external parties on behalf of the patient. To measure the value of the Nurse Care Coordinator, young patients (n=20) were provided with a questionnaire with four Likert scale items. In addition, they received a phone call from a Research Nurse, asking the open-ended question; “What is your opinion of the function of a Nurse Care Coordinator, and what are the areas where the Nurse Care Coordinator could carry out her role better or differently?” RESULTS Both the quantitative results from the questionnaire and the open-ended qualitative responses from the young patients, showed that the function of the Nurse Care Coordinator provided both value and meaning to the young patients. Responses included references to the perception of safety (as opposed to anxiety), a sense of familiarity and comfort (during chaotic and unfamiliar processes), and a constructive approach to patient enquiry (providing help and effective assistance). CONCLUSION The role of a Nurse Care Coordinator has increased focus on the young patients with a brain tumor in the Neurosurgical Clinic. It has also contributed to a higher degree of multidisciplinary workflows around the young patients and great satisfaction for the young patients.